Severe acute and chronic pains mean that various destructive stimuli cause excitation of nociceptor, which is passed by the impulse of nociceptive information transmitting messenger to the central nerve system to cause nociception and algesia. Severe acute and chronic pains include tumor pains, postoperative pains, a variety of recurrent acute and chronic pains and the like. They had been troubled tens of millions of patients and are one big clinical problem currently.
Currently, analgesics broadly used in clinic are generally divided into the following three types: 1) non-steroid-anti-inflammatory analgesics 2) opioid analgesics 3) other non-opioid analgesics, including local anesthetics, antidepressants, antiepileptics and the like.
In case of clinical therapy, opioid analgesics are mainly used, or some non-steroid-anti-inflammatory analgesics are assisted for acute pains and tumor pains. Non-steroid-anti-inflammatory analgesics are seldom used alone for the above pains due to their poor analgesic effect, whereas the side effects of the opioid analgesics such as addiction, respiratory depression and gastric peristalsis decrease, limit their wide use. On the other hand, in the treatment of various chronic non-tumor pains and neuropathic pains, especially pathologic chronic pains, the therapeutic effects of opioid analgesics or non-steroid-anti-inflammatory analgesics are hardly satisfactory. In recent years, in the process of clinical application, some drugs for treating depression, epilepsia and anesthetic drugs are found to have excellent therapeutic effect to alleviate above pains.
Therefore, it is both the main research goal in analgesic field and the heat in innovative medicine research field to find wide spectrum analgesics which maintain strong analgesic effect as well as overcome numerous side effects of opioid analgesics and non-steroid-anti-inflammatory analgesics, to be safely used in clinic. In recent years, some big pharmaceutical companies abroad such as Pfizer, Merck of America etc. invest heavily to develop novel non-opioid analgesics.
Current non-opioid analgesics divided by mechanism mainly include: NMDA receptor antagonists (such as Ketamine), serotonin reuptake inhibitors (such as Tramadol), potassium ion channel openers (such as Flupirtine), cycloxygenase-2 inhibitors (such as Celebrex), calcium ion channel antagonists (such as Ziconotide) and the like. Although these drugs have improvement in addiction and side effects over previous drugs, as reported in detail in, such as, U.S. Pat. No. 6,339,105, U.S. Pat. No. 4,481,205, U.S. Pat. No. 5,760,068, U.S. Pat. No. 5,189,020, but still have certain levels of addiction or high toxic and side effects. For example, Ketamine, Tramadol and Flupirtine still have addiction; Celebrex has latent cardiovascular side effects; Ziconotide can easily cause postural hypotension and the like. Meanwhile, the existing drugs are far from enough to meet the demand of various clinical patients for the pain control, especially for some tumor pains, severe chronic pains and some nerve pains, there are not any proper and safe analgesics at present. Therefore, there is need to develop novel structural non-addictive analgesics with less toxic and side effects and wide therapeutic ranges which are safe in clinical use so as to meet the demand of various patients suffering from pains. Meanwhile, non-opioid analgesics have growing massive market, and large social benefits and economic benefits will be generated if novel analgesics come out.
Selective serotonin reuptake inhibitors (SSRIs) have been confirmed to be effective in various animal and human pain indication tests. It has been demonstrated by lots of investigations that SSRIs not only can strengthen the effect of traditional opioid analgesic, but also have evident analgesic effect over acute pains, inflammatory pains and neuropathic pains in various animal models. For example, (Psychopharmacol. Commun.) 1975, 1: 511-521; Hynes el al., (Pharmacol. Toxicol.) 1999, 85:263-268; Sawynok el al., (Pain) 2000, 85: 311-312; (Expert Opinion on Drug Discovery), 2007, 2: 169-184 and so forth.
Selective 5-HT1A receptor agonists have been confirmed to effectively alleviate pains in animal acute and chronic pain models and inflammatory pain models. For example, (Meth. Find. Exp. Clin. Pharmacol.) 1999, 21: 161-165; Shannon and Lutz (Psychopharmacology) 2000, 149: 93-97; (Eur. J. Pharmacol.) 2004, 497, 285-292 and so forth.
Using selective serotonin reuptake inhibitors in combination with selective 5-HT1A receptor agonists rather than using selective serotonin reuptake inhibitors (SSRIs) alone, have better effect in treatment of chronic pain diseases, or in treatment of other diseases which are allergic to pain signal or algesia, with abnormal pain, enhancing pain sensation, enhancing pain memory and involve hypersensitisation effect. Above conclusion is further confirmed by related investigations, for example, (Prog. Neurobiol.) 2002, 66: 355-474; (Brain Res.) 2004, 1008, 288-292 and so forth.
Endogenous 5-HT generates various pain sensations by acting on 5-HT2A and 5-HT2C receptors of nervous tissue. By employing 5-HT2A antagonists or inverse agonists, various pains, especially acute inflammatory pains and pain allergies caused by various reasons, could be effectively supressed. (Neurochem Int, 2005, 47(6): 394-400. Neuroscience, 2005, 130(2): 465-474. Pain, 2006, 122(1-2): 130-136. Eur J Pain, 2008, In Press, Corrected Proof, Available online 24 July)
It is demonstrated by experiments, Trazodone possessing both 5-HT reuptake inhibitory effect and 5-HT2A antagonistic effect, has definite therapeutic effect towards continuous painful somatoform disorders, the clinical effect of which is better than that of ibuprofen. Combination of 5-HT reuptake inhibitor paroxetine with 5-HT2A antagonist ketanserine could clearly enhance the analgesic effect of the former in animal models (J Pharmacol Sciences, 2005, 97(1): 61-66).
Therefore, novel structural non-opioid analgesics possessing strong inhibitory effect to serotonin reuptake and affinity to 5-HT1A and 5-HT2A receptors, can not only have synergistic pharmaceutical effect to strengthen anti-neuropathic pain activities, but also have lower toxic and side effects. They are important research directions for development of novel anti-neuropathic pain drugs recently, regarding which inventive research is innovative and of important science value.
Serotonin reuptake inhibitors as antidepressants have been widely used in clinic, existing drugs mainly include: (1) selective serotonin reuptake inhibitor (SSRIs), such as Fluoxetine, Paroxetine; (2) specific serotonin reuptake and noradrenergic reuptake inhibitors (NDRIs), such as Mirtazapine; (3) serotonin and noradrenaline dual reuptake inhibitors (SNRIs), such as Venlafaxine and Duloxetine and so forth.
Investigation of antidepressants possessing dual effect of selective serotonin reuptake inhibitor and 5-HT1A receptor agonist is an important direction in this research field recently. Agonistic effect to 5-HT1A receptor can enhance anti-depression activities of serotonin reuptake inhibitors, and combination of the two has found clinical use. A medication of Vilazodone Hydrochloride, possessing the above-described dual target effect, had been approved by FDA to enter into the market in 2011 for treatment of adult depressions, with characteristics of high anti-depression efficiency and rapid onset of action etc. (J Clin Psychiatry. 2009, 70 (3):326-33). Acting on 5-HT2A receptor antagonist can also enhance anti-depression activity by adjusting serotonin levels in nerve synaptic cleft. For example, nefazodone, which possesses serotonin reuptake inhibitory effect and 5-HT2A receptor antagonistic effect, has been confirmed to have clear anti-depression effects.
Therefore, novel antidepressants, which have multiple effects of strong inhibitory effect to serotonin reuptake and affinity to 5-HT1A and 5-HT2A receptors, can not only have strong anti-depression activities, but also have rapid onset of action and lower toxic and side effects etc. They are popular research directions for conducting and developing novel antidepressants recently, regarding which inventive research is innovative and of important science value.